The objective of this investigation is to provide a better understanding of the pathophysiology of diabetic cerebral angiopathy. Since functional angiopathy probably occurs prior to morphologically demonstrable lesions, the cerebral circulation will be studied at various intervals following the induction of diabetic mellitus with alloxan or streptozotocin in rats. Functional changes in the microvasculature and microcirculation will be evaluated on the surface of the cortex supplied by the middle cerebral artery using in vivo microscopic and microphysiologic methods. Light and electron microscopic, biochemical, and neuroanatomical methods will be used to relate the observed changes in the circulation and permeability to changes in the morphology of the vascular wall. In vitro analysis of alterations in the contractile mechanisms of vascular smooth muscle will be used to relate changes in vascular reactivity seen in vivo to alterations in the structure and chemistry of the vascular wall and its environment. By providing an improved understanding of the patho-physiology of diabetic angiopathy in experimental animals, it is hoped that this investigation will help to provide the basis for improved therapy of the cerebral vascular dysfunction associated with diabetes mellitus in humans.